rs1553257236

chr1-113896264-AGTAATACAACAAAC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001253852.3(AP4B1):c.1490_1503del(p.Arg497LeufsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP4B1 NM_001253852.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.29

Genes affected

AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-113896264-AGTAATACAACAAAC-A is Pathogenic according to our data. Variant chr1-113896264-AGTAATACAACAAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 434228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253852.3	c.1490_1503del	p.Arg497LeufsTer26	frameshift_variant	8/10	ENST00000369569.6
AP4B1-AS1	NR_125965.1	n.415-1601_415-1588del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.1490_1503del	p.Arg497LeufsTer26	frameshift_variant	8/10	1	NM_001253852.3	P1
AP4B1-AS1	ENST00000419536.1	n.247-1601_247-1588del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 47 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 02, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553257236; hg19: chr1-114438886;